Current Research in Green and Sustainable Chemistry 4 (2021) 100174

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Current Research in Green and Sustainable Chemistry

journal homepage: www.elsevier.com/journals/
current-research-in-green-and-sustainable-chemistry/2666-0865

Green synthesis interventions of pharmaceutical industries for

sustainable development
Mohit Mishra a, Mansi Sharma a, Ragini Dubey b, Pooja Kumari a, Vikas Ranjan a, Jaya Pandey b, *
a
Amity Institute of Biotechnology, Amity University Chhattisgarh, India
b
Amity School of Applied Sciences Lucknow, Amity University, Uttar Pradesh, 226016, India

A R T I C L E I N F O A B S T R A C T

Keywords: Green chemistry nowadays is surpassing the idea of being a sheer lab inquisitiveness into the large-scale phar-
Green synthesis maceutical application in industries. However, industries being one of the most dynamic area, always remain in
Pharmaceutical industry the forefronts of any substantial changes. These changes in the terms of innovative ideas, conventional feed
Sustainability
stocks, safer raw materials, and alternative mechanisms in laboratories at pilot scale seems fascinating to apply in
industries. The purpose of this review is to present a selective overview of the green synthesis in the pharma-
ceutical industries where the green chemistry practices have been applied successfully. The green practices in the
synthesis of drugs demonstrated in the review are some examples chosen based upon the optimal yield, solvent
selection, biocatalysts and regioselectivity of some pharmaceutical products produced at large industrial scales.
The objective is to overview the status of the integration of the green chemistry in the pharmaceutical industries
and its problem and challenges with the emphasis of a way forward in this direction.

1. Introduction Chemical manufacturer generates significant amounts of waste by-

Green Synthesis aims to optimize consumption, reduce energy waste,
and use renewable energy sources for the power supply. Despite of the
fact that the pharmaceutical companies are the leading contributors in
the world economy with total revenue of 1.27 trillion U.S. dollars, it has
also been one of the fundamental causes in the carbon footprint by
producing approximately 1.9 Mt CO2 [1]. Though the seeds of imple-
menting the idea of environment protection originated a decade ago,
many of them failed in execution due to the lack of collaborative efforts
from the industries. The Industrial Nations have always been looking to
manage output and identify processes to reduce their impact on the
environment, however, neither of the former ideas satisfied these in-
dustries [2]. The goal of every pharma company has always been an
assurance to deliver revolutionary drugs to enhance the standard of
living across the world. To accomplish this goal in an environmentally
friendly way, the companies need to progress from the traditional syn-
thetic processes to a present-day innovative mechanism [3]. From small
industries to large corporations have already moved forward to adapt
sustainable way by modifying the chemical manufacturing processes to
green synthesis of the products involving the principles of green chem-
istry (Fig. 1).
products and pollutants, like depleted reagents, air pollutants and
contaminated solvents. Pharmaceutical industries are a significant
contributor of all these factors [4]. It is extremely important to identify
gaps and work necessary to develop tailored education and training
material to promote the uptake of green and sustainable methodologies
required in the bio-process units such as in the pharmaceutical industries
to reduce its impact on the environment. The current scenario of green
chemistry is at high command [5–8].
In recent decades, the pharmaceutical industries have evolved to-
wards a different way to tackle the development of those processes that
deals with problems such as pollution, the use of limited environmental
resources and renewable sources with sustainability. So, the adoption of
green chemistry principles could be viewed as an additional hurdle.
There is growing awareness about environmental pollution and
improved testing methodologies, the pharmaceutical sector is facing
increased pressures to improve both its manufacturing efficiency and the
impacts of its products. Capital investment also prevents the commer-
cialization of a green technology [9–11]. The commercialization of green
processes also requires many changes in all part of the long and global
supply chain. Green is not always economical but other way around is
proven right in a holistic sense (Fig. 2).

* Corresponding author.
E-mail address: jpandey@lko.amity.edu (J. Pandey).

https://doi.org/10.1016/j.crgsc.2021.100174
Received 22 July 2021; Received in revised form 13 September 2021; Accepted 18 September 2021
Available online 20 September 2021
2666-0865/© 2021 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
M. Mishra et al.
The industry is already challenged with issues such as the intellectual
property demands and fail fast requirements. Industries at the same time
has also to consider Safety & Occupational Health Management of the
people involved in the process [12].
Although, the pharma companies are starting to realize the effi-
ciencies and cost-savings that the green synthesis offers and a incorpo-
rating them into application. In addition, green chemistry significantly
reduces the dependence of these industries on the fossil fuels but still
there is lack of meaningful Government subsidy on alternative energy
resources usage and set ups for Pharmaceutical industries [13].
One of the additional problems with the pharmaceutical companies is
the new regulations for environmental pollution of water sources, from
both industrial waste as well as from the traces of the drugs and medic-
inal products which are released in the water bodies as municipal liquid
waste. It has been found that even low concentrations of drugs and drug
metabolites heavily pollute lakes, rivers, and coastal regions. As well as
Drugs in higher concentrations severely affect aquatic organisms like
fish, and other benthic organisms. Mostly, the pharmaceutical manu-
facturers are attentive of these facts and take the environmental problems
2
Current Research in Green and Sustainable Chemistry 4 (2021) 100174
Fig. 1. Twelve Principles of Green Chemistry (1)
Prevent waste: Designing chemical synthesis to
avoid waste. Reduce the waste production as much
as possible. Do not leave the waste to be treated (2)
Maximize atomic economy: Designing the syn-
thesis in such a way that the final product contains
the maximum percentage of the initial material.
Little or no atom is wasted. (3) Design less
dangerous chemical synthesis: Designing the
synthesis that either use, or generate substances
with minimal or no toxicity for humans or the
environment. (4) Design safer chemicals:
Designing chemicals which are fully effective but
have minimal or no toxicity. (5) Use safer solvents
and reaction conditions: Avoid the use of sepa-
rating agents, solvents or other auxiliary chemicals.
If required, use the safer ones. (6) Increase energy
efficiency: Perform chemical reactions at room
temperature and pressure whenever and wherever
possible. (7) Use renewable raw materials: Use
initial materials which are renewable rather than
exhaustible ones. Renewable raw material sources
are usually agricultural products or other bio-waste
or waste from other processes; sources of exhaust-
ible raw materials include the fossil fuels (oil, nat-
ural gas or coal) or mining activities. (8) Avoid
chemical derivatives: Avoid the use of any tem-
porary changes or protective groups, if possible.
These derivatives use additional reagents and
generate a lot of, often avoidable, waste. (9) Use
catalysts, stoichiometric non-reagents: Minimize
the waste by using catalytic reactions. Catalysts are
very effective in smaller quantities and can perform
a single reaction multiple times. They are preferable
over the stoichiometric reagents, which are required
in excess and can react only once. (10) Design
chemicals for degradation: Design those chemicals
which reduce harmful substances after their use so
that they do not accumulate in the environment.
(11) Real-time pollution prevention: Include an
in-process control and monitoring, in real time
during the synthesis to reduce or eliminate the for-
mation of harmful by-products. (12) Minimize the
risk of accidents: Design such chemicals with their
physical forms (solid, liquid or gaseous) to reduce
the potentials of chemical accidents including fires,
explosions and releases into the environment
(Bruno, 2020). (For interpretation of the references
to colour in this figure legend, the reader is referred
to the Web version of this article.)
very seriously however the current regulations are not optimal for in-
dustries [14–17].
The major issue identified for application of green synthesis is that the
existing green feedstock material are not easily accessible. This is because
either they are not at the correct level, i.e. too detailed or too basic, or it is
difficult to find them. Sometimes they are not in a user-friendly format or
not industry specific [18]. However, at many places pharmaceutical in-
dustries have successfully applied the principles and techniques of Green
Chemistry to produce drugs (Fig. 3). Some of the successful end products
and technologies which became dominant and recognised in the recent
years as follows:
(A) Green solvent: With the aim to reduce hazardous solvents with
more green solvents like Sertraline Hydrochloride, is synthesized
where the chemical reagents like toluene, hexane, THF and metal
salts like TiCl4 were consumed [19]. These solvents were replaced
by greener solvent like water also removal of metal salts and Pd/C
catalyst gave more selective and greener protocol (Fig. 4).
M. Mishra et al.
Fig. 2. Problems (A) Pharma Industries (B) Chemical reactions (C) Waste generation leading to water and land pollution (D) Air pollution (E) Environmental
Pollution. Challenges for Green Practices (F) Mass production and Profit (G) Environmental Laws (H) Design Implementation (I) IPR regulations. (For interpretation
of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
(B) Improved design ABT-546 - The process for the synthesis of the
endothelin-A antagonist ABT-546 provides an excellent example
(Cue et al., 2009). A cognate strategy was implemented in
developing a selective and economical method for catalytic pro-
cess. This method is usually the most effective solution where non-
linearity arises from prochiral starting material (Fig. 5). Although
a polymerized route was developed to prepare the racemic
3
Current Research in Green and Sustainable Chemistry 4 (2021) 100174
Fig. 3. Awards for Green Practices by Pharma In-
dustries (A) for synthesizing a new diabetes drug,
Januvia with an improved productivity of 56%
compared to the existing equipment, overall
10–13% increased yield and an overall reduction of
19% in waste generation (J.J. Song, R.P. Frutos, T.
Tampone, C.H. Senanayake, D. Krishnamurthy,
2012) (B) for conceiving a biosynthetic way to
manufacture drug “Simvastatin”. Customer feedback
confirmed that bio catalytically synthesized simva-
statin meets their needs (Ajoy Basa &, Sarmistha
Basak, 2020): (C) The industry adopts batch flow
hybrid approaches for safe and robust manufactur-
ability for the green chemistry cover in processing
mass intensity, atom efficiency, effluent water and
hazardous waste management. (For interpretation of
the references to colour in this figure legend, the
reader is referred to the Web version of this article.)
pyrrolidine core of ABT-546, it required following resolution with
D-tartaric acid. But after several recrystallizations only 40%
resolved tartrate salt was obtained.
There is a definite need a search for an asymmetric synthesis of the
pyrrolidine core to support various upcoming clinical trials. After careful
screening and analysis, a catalytic, highly enantioselective conjugate-
M. Mishra et al.
addition was formed in which the b-ketoester anion 15 was added to
nitroolefin 16 via catalysis with 4 mol % bis(oxazoline) - Mg (OTf)2
amine complex. The ability to attain 88% selectivity in this addition
allowed less dependence on the tartrate salt for upgrading the chiral
purity. There is a peculiar advantage to choosing green solvents in the
final steps of a drug preparation as any residual in the API produce less
concern [20].
The formation of ABT- 546 was organized to use water as a co-solvent
for the last three steps. The tartrate salt was broken with potassium
carbonate (K2CO3) in THF/water, the free base residing in the THF layer.
Then, bromoacetamide was added to the THF solution of free base, along
with aqueous NaHCO3, and the reaction was heated until alkylation was
complete. The product in the THF layer was diluted with ethanol after
separation. Finally, aqueous NaOH was used for saponification. The three
step/one pot sequence provided the free base of ABT-546 in excellent
yield (96%) without the need for solvent removal and extraction.
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Current Research in Green and Sustainable Chemistry 4 (2021) 100174
Fig. 4. Green solvent process in the synthesis of
Sertraline Hydrochloride,a feasible study results that
a proof-of-concept was carried out in the year 2004
by Pfizer, Inc. where the drug sertraline hydrochlo-
ride (C17H18Cl3N) also known as Zoloft, a selective
inhibitor of serotonin reuptake which is used for the
treatment of depression which was synthesized by
conventional synthetic route. The chemical reagents
like toluene, hexane, THF and metal salts like TiCl4
were consumed (Taber et al., 2004). Removal of
metal salts and Pd/C catalyst gave more selective and
greener protocol. (For interpretation of the refer-
ences to colour in this figure legend, the reader is
referred to the Web version of this article.)
Fig.5. Green design process for the synthesis of
ABT-546. The conventional method utilized racemic
pyrrolidine core of ABT-546, followed by resolution
with D-tartaric acid (Yield 40%). Green synthesis
involving use of catalyst and highly enantioselective
conjugate-addition forming the b-ketoester anion
with nitroolefin resulted in 88% selectivity. In the
final steps water was used as a co-solvent. ABT-546
in excellent yield (96%) was obtained without the
need for solvent removal and extraction (Cue et al.,
2009). (For interpretation of the references to colour
in this figure legend, the reader is referred to the
Web version of this article.)
(C) Biocatalysts- The Drug Paroxetine - The overall yield was almost
double of the previously used conventional method, leading to a
greener, shorter, and more cost-efficient way. The most important
step was to apply protease enzyme which was regioselectivity
hydrolyzed an ester group.
Atorvastatin side chain process is a great example of using Bioen-
gineering and enzymes for selective transformations.
Biosynthetic way to manufacture drug, Simvastatin, is one of the
example of biocatalysts. The major notable advantage in the process is
the continuous processing through the reactors where the compounds
stay for short period of time [21]. It has vastly minimized the
manufacturing footprint which helped in the easy processing of sensitive
substances (Fig. 6).
Synthesis of a new diabetes drug, Januvia with an improved pro-
ductivity of 56% compared to the existing equipment, Overall 10–13%
M. Mishra et al.
Fig.6. Green catalyst synthesis of Atorvastatin. Three biocatalytic enzymes namely keto-reductase, glucose dehydrogenase and halohydrin dehalogenase improve
the yield and significantly reduced the waste production by regioselective reaction of the chiral intermediate hydroxyl nitrile. (For interpretation of the references to
colour in this figure legend, the reader is referred to the Web version of this article.)
increased yield and an overall reduction of 19% in waste generation.
Below is a table describing the case studies of different drugs along
with their outcomes (Fig. 7) and the structures of industrially manufac-
tured drug molecules prepared by green synthesis methods (Fig. 8)
2. Conclusion
The challenges being perceived in application of green and sustain-
able chemistry needs a wide variety of addressal. Particularly training on
basic level of green chemistry which is designed to give a good basis in
key concepts of process excellence in design, biocatalysis, selection of
solvents, reagents, tools and operational excellence. Judicious use of
renewable energy resources and managing water efficiency and waste
generation has to be taken into consideration at the same time
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Current Research in Green and Sustainable Chemistry 4 (2021) 100174
Fig. 7. Advantageous outcomes of Green practices in
Pharmaceuticals companies: (1)Sertaline Hydrochlo-
ride, 2005, used for Clinical depression, developed
by Pfizer Nurettin Menges (2017).(2) Pregabalin,
2005, used for Neuropathic pain and Epilepsy,
developed by Pfizer, Dunn, P.J., Hettenbach, K., Kel-
leher, P. and Martinez, C.A. (2010).(3) Sitagliptin,
used in Type-2 Diabetes, developed by Merck and
Codexis, J.J. Song, R.P. Frutos, T. Tampone, C.H. Sen-
anayake, D. Krishnamurthy (2012).(4) Doramectin
(under commercial, trade name Dectomax), used
for the treatment of parasites, developed by Pfizer,
Valavanidis, Athanasios & Vlachogianni, Thomais.
(2012).(5) Ibuprofen, used as Anti-inflammatory,
developed by BASF, Cann, M.C. and Connelly, M.E.
(2000).(6) Gemifloxacin, used as Antibiotic, devel-
oped by Merck, Valavanidis, Athanasios & Vlacho-
gianni, Thomais. (2012). (7) Atorvastatin, used for
prevention of cardiovascular disease, developed by
Pfizer, Valavanidis, Athanasios & Vlachogianni,
Thomais. (2012). (8) Simvastatin, used for Treat-
ment of high cholesterol, developed by Codexis, Ajoy
Basa &, Sarmistha Basak(2020). (For interpretation of
the references to colour in this figure legend, the
reader is referred to the Web version of this article.)
implementing carbon emission reduction should also be in focus.
Although the concept of Green Chemistry has been generally accepted by
the scientific community, the technical Green Chemistry evolution is yet
to achieve with the appropriate attention and effort which only possible
through education and awareness.
Transforming the conventional chemical companies into a sustainable
ones requires significant change. However, this requires a foundation of
cooperation between education, politics, economics, interdisciplinary
commitment, equity, metrics, regulation, and awareness. Certainly,
many research centers and universities has been moving for years to-
wards greener chemistry that is now slowly starting to invest in various
industrial realities. However, much needs to be done not only to carry out
research, but also to change the way we approach chemistry and syn-
thesis, what it can bring in terms of well-being and technological and
M. Mishra et al.
Fig. 8. Drugs of Green Synthesis (1) Simvastatin: Lower blood level, LDL, Reducing heart attack; (2) Pregabalin: Antiepileptic; (3) Ibuprofen: Pain Killer; (4)
Paroxetine: Antidepressant; (5) Atorvastatin: Low density cholesterol level, Ani cardiovascular agent; (6) Doramectin: Veterinary Drug; (7) Januvia: Anti-diabeteic; (8)
Gemifloxacin: Antibacterial; (9) Sitagliptin: Treat High blood Sugar.
social progress. Eventually, a time will come when there will be no need
to emphasize on green chemistry to pharmaceutical chemists as it will be
inculcated into the natural course of action, when the utmost benefit to
the company, patient, and most importantly the environment.
Currently green chemistry has gained a prominence in the global
stage. In addition to solving many environmental issues, it also generates
quality products with minimum residues of toxic materials. Analysing the
overall state of the pharmaceutical industry and the complications faced
including the environmental concerns, expensive products, and many
other such issues, it can be concluded that Green chemistry is an inno-
vative solution to raise the standard of living and minimize the envi-
ronmental issues. As a result, carbon and water foot prints can be
reduced, hazardous chemicals and solvents can be reduced and replaced
by renewable green solvents and feedstocks. Green Chemistry has the
potential to transform the pharmaceutical industry and drug
manufacturing in the future. It provides benefit both environmentally
and economically. It will result in transforming the traditional pharma-
ceutical industries into sustainable ones and sustainability of the
environment.
Credit authorship contribution statement
Mansi Sharma, Pooja Kumari, Vikas Ranjan: Literature survey,
Data Curation, Writing original draft. Mohit Mishra*: Conceptualiza-
tion, Supervision, Writing original draft, review and editing. Jaya Pan-
dey*: Formal Analysis, Supervision, Final draft. Ragini Dubey:
Visualization, Finishing Review and Editing.
Declaration of competing interest
The authors declare no conflict of interest.
Acknowledgement
Authors are thankful to Amity School of Applied Sciences, Amity
University Uttar Pradesh Lucknow Campus and Amity Institute of
Biotechnology, Amity University Chhattisgarh for help in supporting
research.
6
Current Research in Green and Sustainable Chemistry 4 (2021) 100174
References
[1] R. Bandichhor, Hazardous Reagent Substitution: A Pharmaceutical Perspective
Green Chemistry Series 52 (2018).
[2] A. Dhasmana, S. Uniyal, V. Kumar, S. Gupta, K.K. Kesari, S. Haque, M. Lohani,
J. Pandey, Environmental Biotechnology: for Sustainable Future, 2018.
[3] N. Singh, J. Pandey, Advances in henry reaction: a versatile method in organic
synthesis, Mini-Reviews Org. Chem. 16 (2019) 1–12, 0.2174/
1570193X16666190214150144.
[4] M. Mahender, B. Yakambaram, J. Pandey, E.R.R. Chandrashekar, L. Amarnath
Reddy, A. Jayashree, R. Bandichhor, Stereoselective synthesis for potential isomers
of ticagrelor key starting material, J. Heterocycl. Chem. 56 (2019) 2866–2872.
[5] G. Arora, R. Shrivastava, P. Kumar, D. Krishnamurthy, R.K. Sharma, A.S. Matharu,
M. Rizwan, Recent advances made in the synthesis of small drug molecules for
clinical applications: an insight, Curr. Res. Green and Sustain. Chem. 4 (2021)
2666–2865, doi.org/10.1016/j.crgsc.2021.100097.
[6] N. Anderson, The impact of process chemists and engineers on green chemistry,
Org. Process Res. Dev. 12 (2008) 1019–1020.
[7] Bruno, Green Chemistry: Criteria and Applications, Lifext Research Group, 2020.
[8] M.C. Cann, M.E. Connelly, Real-world Cases in Green Chemistry, American
Chemical Society, 2000.
[9] B.W. Cue, J. Zhang, Green process chemistry in the pharmaceutical industry, Green
Chem. Lett. Rev. 2 (2009) 193–211.
[10] P.J. Dunn, K.P. Hettenbach, C.A. Martinez, The development of a green, energy
efficient, chemoenzymatic manufacturing process for pregabalin, Green. Chem.
Pharma. Indus. (2010) 161–177, https://doi.org/10.1002/9783527629688.ch8.
[11] E. Silva, F.C.S. Pires, M.C.R. Ferreira, I.Q. da Silva, G.C.M. Aires, T.M. Ribeiro, Case
studies of green solvents in the pharmaceutical industry, Green. Sustain. Process.
Chem. Environ. Eng. Sci. (2021) 151–159, https://doi.org/10.1016/B978-0-12-
821885-3.00009-8.
[12] reportGlobal Pharmaceuticals Market Report 2021-2030 Featuring Major Players -
Pfizer; F. Hoffmann-La Roche Ltd; Sanofi; Johnson & Johnson and Merck & Co
(prnewswire.com).
[13] J. Agbenyenga, Sustainable Chemistry in the Pharma Industry: Greener Pastures for
Those Who Innovate, CAS - Division of American Chemical Society, 2018. https
://www.cas.org/resources/blog/sustainable-chemistry-pharma-industry-greene
r-pastures-those-who-innovate.
[14] S. Koenig, Scalable Green Chemistry: Case Studies from the Pharmaceutical
Industry, CRC Press, 2013.
[15] L. Summerton, R.J. Taylor, J.H. Clark, Promoting the uptake of green and
sustainable methodologies in pharmaceutical synthesis: CHEM21 education and
training initiatives, Sustain. Chem. Pharmacy. 4 (2016) 67–76, https://doi.org/
10.1016/j.scp.2016.09.003.
[16] N. Menges, The role of green solvents and catalysts at the future of drug design and
of synthesis, Green Chem. (2017), https://doi.org/10.5772/intechopen.71018.
[17] A.J. Sobral, Synthesis of meso-diethyl-2, 2'-dipyrromethane in water. An
experiment in green organic chemistry, J. Chem. Educ. 83 (11) (2006) 1665–1666.
[18] Summary of Fermentation Process, Brought about by Directed Evolution of Three
Biocatalysts www.codexis.com/wt/page/pr_1167522017.
M. Mishra et al.
[19] G.P. Taber, D.M. Pfisterer, J.C. Colberg, A New and Simplified Process for Preparing
N-[4-(3, 4-dichlorophenyl)-3, 4-dihydro-1 (2H)-naphthalenylidene] methanamine
and a telescoped process for the synthesis of (1 S-cis)-4-(3, 4-dichlorophenol)-1, 2,
3, 4-tetrahydro-N-methyl-1-naphthalenamine mandelate: key intermediates in the
synthesis of sertraline hydrochloride, Org. Process Res. Dev. vol. 8 (3) (2004)
385–388.
Current Research in Green and Sustainable Chemistry 4 (2021) 100174
[20] A. Valavanidis, T. Vlachogianni, Pharmaceutical industry and green chemistry: new
developments in the application of green principles and sustainability,
Pharmakeftiki 24 (3) (2012) 44–56.
[21] V. Vesela, B. Cue, Benchmarking green chemistry adoption by “big pharma” and
generics manufacturers, Benchmark Int. J. 24 (2017), https://doi.org/10.1108/BIJ-
01-2016-0003.